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Infection and Immunity, March 2003, p. 1281-1287, Vol. 71, No. 3
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.3.1281-1287.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Analysis of the Role of Bphs/Hrh1 in the Genetic Control of Responsiveness to Pertussis Toxin

Department of Medicine, University of Vermont School of Medicine, Burlington, Vermont 05405,¹ Department of Veterinary Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61802,² Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan,³ Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104⁴

Received 18 September 2002/ Returned for modification 15 November 2002/ Accepted 4 December 2002

	ABSTRACT

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In vivo intoxication with Bordetella pertussis toxin (PTX) elicits a variety of physiological responses including a marked leukocytosis, disruption of glucose regulation, adjuvant activity, alterations in vascular function, hypersensitivity to vasoactive agents, and death. We recently identified Bphs, the locus controlling PTX-induced hypersensitivity to the vasoactive amine histamine, as the histamine H₁ receptor (Hrh1). In this study Bphs congenic mice and mice with a disrupted Hrh1 gene were used to examine the role of Bphs/Hrh1 in the genetic control of susceptibility to a number of phenotypes elicited following in vivo intoxication. We report that the contribution of Bphs/Hrh1 to the overall genetic control of responsiveness to PTX is restricted to susceptibility to histamine hypersensitivity and enhancement of antigen-specific delayed-type hypersensitivity responses. Furthermore, the genetic contribution of Bphs/Hrh1 to vasoactive amine sensitization is specific for histamine, since hypersensitivity to serotonin was unaffected by Bphs/Hrh1. Bphs/Hrh1 also did not significantly influence susceptibility to the lethal effects, the leukocytosis response, disruption of glucose regulation, and histamine-independent increases in vascular permeability associated with in vivo intoxication. Nevertheless, significant interstrain differences in susceptibility to the lethal effects of PTX and leukocytosis response were observed. These results indicate that the phenotypic variation in responsiveness to PTX reflects the genetic control of distinct intermediate phenotypes rather than allelic variation in genes controlling overall susceptibility to intoxication.

	INTRODUCTION

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Pertussis toxin (PTX) is a major virulence factor of Bordetella pertussis, the causative agent of whooping cough (9). The holotoxin is a hexameric protein that conforms to the A/B model of bacterial exotoxins (31). The A subunit is an ADP-ribosyltransferase which affects signal transduction by ribosylation of the subunit of trimeric Gi proteins while the B oligomer binds cell surface receptors on a variety of mammalian cells (19, 31). PTX, when administered in vivo, elicits a large number of physiological responses including disruption of glucose regulation, leukocytosis, adjuvant activity, increased vascular permeability associated with alteration of blood-tissue barrier functions, sensitization to vasoactive agents, and death (12, 24, 27, 29, 44).

Inbred strains of mice differ in susceptibility to vasoactive amine challenge following PTX sensitization in that genetically susceptible strains die from hypotensive and hypovolemic shock whereas resistant strains do not (29, 43). Bphs, the gene controlling susceptibility to PTX-induced hypersensitivity to histamine, was previously mapped to the central region of mouse chromosome 6 (39) and recently identified as being the histamine H₁ receptor (Hrh1) (25). As the first step in positionally cloning Bphs, we generated a panel of interval-specific recombinant congenic lines by using marker-assisted selection to introgress the susceptible SJL/J Bphs allele (Bphs^s) onto the resistant C3H/HeJ background. One particular line, C3H.SJL-Bphs^sD, was studied in detail and found to be as susceptible to histamine sensitization as were SJL/J mice over a wide range of histamine doses. Since the relationship between the genetic control of susceptibility to vasoactive amine sensitization and the plethora of phenotypes associated with PTX intoxication is unclear, we utilized C3H.SJL-Bphs^sD congenic mice and mice with a disrupted Hrh1 gene to examine the role of Bphs in the genetic control of a number of these phenotypes. Our results demonstrate that phenotypic variation in responsiveness to PTX reflects the genetic control of specific intermediate phenotypes rather than susceptibility and resistance to intoxication in general and that Bphs appears to be restricted to the genetic control of histamine sensitization and the adjuvant activity of PTX.

	MATERIALS AND METHODS

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Animals. SJL/J and C57BL/6J mice were purchased from the Jackson Laboratory (Bar Harbor, Maine). B6.129P-Hrh1^tm1Wat, C3H/HeJ (C3H.SJL-Bphs^hD), and C3H.SJL-Bphs^sD (homozygous and heterozygous) congenic mice, generated by breeding heterozygous C3H.SJL-Bphs^s/hD mice (25), were produced in either the animal facilities at the College of Veterinary Medicine, University of Illinois, Urbana-Champaign, or at Charles River Laboratories (Wilmington, Mass.). Animals were maintained in accordance with the Animal Welfare Act and the Public Health Service Policy on the Humane Care and Use of Laboratory Animals.

PTX in vivo intoxication. Mice were injected intravenously (i.v.) with purified PTX (List Biological Laboratories, Inc.) in 0.025 M Tris buffer containing 0.5 M NaCl and 0.017% Triton X-100, pH 7.6. Control animals received carrier.

Virulence testing. Mice were injected i.v. with PTX on day 0, and mortality was recorded as a function of time postchallenge.

Blood analysis. All laboratory blood tests were performed by the Diagnostic Laboratory of the College of Veterinary Medicine, University of Illinois, Champaign-Urbana. Twenty-four-hour fasting blood glucose determinations and total leukocyte (WBC) counts were performed at 3 days post-PTX injection. Responsiveness to epinephrine was assessed by determining blood glucose levels 30 min after the intraperitoneal (i.p.) injection of 5.0 µg of epinephrine in 0.2 ml of phosphate-buffered saline (PBS).

Tissue vascular permeability determinations. Bovine serum albumin (BSA) was used as the radiolabeled protein tracer to measure vascular permeability (23). BSA was radiolabeled with ¹²⁵I by the chloramine T method. The specific activity of the labeled ¹²⁵I-BSA was 2.0 µCi/mg. For tissue permeability measurements, mice were injected i.v. with 0.5 ml (1.0 µCi) of ¹²⁵I-BSA in PBS at a concentration of approximately 2 mg/ml. Changes in tissue permeability were determined 3 days following i.v. injection of either carrier or PTX. After 1 h, the animals were killed, 100 µl of blood was collected, and the brains and samples of striated thigh muscle were collected. The tissues were thoroughly rinsed with PBS, blotted dry, and weighed, and the amount of ¹²⁵I-BSA in each specimen and blood sample was determined. A permeability index was calculated by dividing the ¹²⁵I-BSA counts per minute per gram of tissue by the ¹²⁵I-BSA counts per minute per milliliter of blood.

Vasoactive amine sensitivity testing. Histamine and serotonin hypersensitivities were determined by i.v. injection of histamine or serotonin (milligrams per kilogram of body weight [dry weight], free base) suspended in PBS. Deaths were recorded at 30 min and 12 h postchallenge. The results are expressed as the number of deaths over the number of animals studied.

Enhancement of antigen-specific delayed-type hypersensitivity (DTH). Mice were injected with 0.05 ml of complete Freund's adjuvant (CFA) consisting of equal volumes of CFA (200 µg of Mycobacterium tuberculosis H37Ra) and ovalbumin (OVA) or myelin oligodendrocyte glycoprotein peptide 35-55 (MOG 35-55) in saline (1.0 mg/ml) in the left footpad and 0.025 ml of emulsion at the base of the tail and scruff of the neck. Immediately thereafter, each animal received PTX by i.v. injection. Seven days later the average thickness of the right pinna was determined by taking three measurements with a spring-loaded micrometer. Subsequently, each pinna was injected with 10 µl of physiological saline containing 1.0 mg of OVA or MOG 35-55/ml. Ear thickness measurements were taken at various times postchallenge, and the corrected average thickness was determined.

Statistical methods. A two-way (5 x 2) analysis of variance (ANOVA) was used to compare WBC counts among the five strains and across two treatment conditions (carrier and PTX). Fasting blood glucose levels, with and without epinephrine treatment, were examined by a three-way (5 x 2 x 2) repeated-measure ANOVA given the five strains and two treatment conditions. The permeability index was examined by a three-way (3 x 2 x 2) repeated-measure ANOVA since correlated data were obtained from two different anatomic sites from three strains and two conditions. Ear thickness changes postchallenge were examined by repeated-measure ANOVA with orthogonal decomposition of the time effects.

	RESULTS AND DISCUSSION

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PTX toxicity. SJL/J mice exhibited greater sensitivity to the toxic effects of PTX than did C3H/HeJ and C3H.SJL-Bphs^sD mice (Fig. 1). For SJL/J mice deaths were first observed at 4 days postinjection (20%), increasing to 80% by day 6 through day 15. Similarly, mortality was delayed in C3H/HeJ (20%) and C3H.SJL-Bphs^sD (20%) mice until days 6 and 4, respectively. However, compared to SJL/J mice no increase in incidence was observed through day 15. These results establish that SJL/J mice are more sensitive to the toxic effects of PTX than are C3H/HeJ and C3H.SJL-Bphs^sD mice and that Bphs/Hrh1 alleles do not play a role in controlling susceptibility to the toxic effects of PTX. The time to death and mortality following intoxication with PTX are similar to those reported previously at corresponding doses (26, 30).

View larger version (12K): [in this window] [in a new window]   FIG. 1. Mortality of SJL/J (), C3H/HeJ (), and C3H.SJL-BphssD () mice injected i.v. with 2.5 µg of PTX (List Biological Laboratories, Inc.) in 0.025 M Tris buffer containing 0.5 M NaCl and 0.017% Triton X-100, pH 7.6. Five mice were injected per test group. Mice were monitored daily for viability, and the data are expressed as the cumulative percent mortality versus the day postinjection.

View larger version (12K): [in this window] [in a new window]   FIG. 2. Leukocytosis response in PTX-treated SJL/J, C3H/HeJ, C3H.SJL-BphssD, C57BL/6J, and B6.129P-Hrh1tm1Wat mice. Mice were injected with carrier (open bars) or 200.0 ng of PTX (solid bars) on day 0. Three days later the animals were killed, blood was collected in EDTA, and total WBC counts were determined. Units are expressed as 10-3/µl of blood ± standard deviations. Due to the unequal variances observed for the WBC counts among the 10 groups, a natural logarithm transformation was used to stabilize the variances. The two-way ANOVA indicated that there were significant differences between mouse strains (P < 0.0001) and between PTX- and carrier-treated mice (P < 0.0001). Multiple comparisons indicated that the WBC count for the SJL/J strain was higher than those for C3H/HeJ and C3H.SJL-BphssD mice. Similarly, both C57BL/6J and B6.129P-Hrh1tm1Wat mice also had higher counts than did C3H/HeJ and C3H.SJL-BphssD mice. All other paired comparisons were not significant.

Hypoglycemia and refractivity to epinephrine-induced hyperglycemia. All strains studied were susceptible to PTX-induced hypoglycemia and were equally refractory to the effects of epinephrine (Table 1). No significant difference was observed between either C3H/HeJ and C3H.SJL-Bphs^sD or C57BL/6J and B6.129P-Hrh1^tm1Wat mice, indicating that Bphs/Hrh1 does not play a role in controlling these two responses. Additionally, there was no difference among the strains with respect to epinephrine-induced hyperglycemia in carrier-treated control mice.

Vascular permeability changes elicited by PTX. No significant differences were observed in the vascular permeability of SJL/J, C3H/HeJ, and C3H.SJL-Bphs²D carrier-treated mice (Fig. 3). In contrast, all three strains exhibited a significant increase in peripheral and central nervous system (CNS) vascular permeability following PTX treatment (Fig. 3). Interestingly, SJL/J mice exhibited a significantly greater increase in both peripheral (7.1 ± 1.1) and CNS (4.9 ± 0.8) vascular permeability than did C3H/HeJ (striated thigh muscle, 5.6 ± 0.8; brain, 3.7 ± 0.9) and C3H.SJL-Bphs^sD (striated thigh muscle, 5.7 ± 0.9; brain, 3.8 ± 0.8) mice. These results are consistent with previous reports indicating that in vivo exposure to B. pertussis (1, 18) or intoxication with PTX leads to increased peripheral and CNS vascular permeability (21, 23, 30) and corroborate reports indicating that SJL/J mice are hyperresponsive in this regard (47, 48). Importantly, no difference in either peripheral or CNS vascular permeability was seen between C3H/HeJ and C3H.SJL-Bphs^sD mice, indicating that Bphs/Hrh1 alleles do not control increased vascular permeability and that other genetic factors are presumably involved.

View larger version (16K): [in this window] [in a new window]   FIG. 3. PTX-induced vascular permeability changes in striated thigh muscle (A) and brain (B) of SJL/J, C3H/HeJ, and C3H.SJL-BphssD mice. Mice were injected i.v. with either carrier (open bars) or 200.0 ng of PTX (solid bars) on day 0. Three days later 0.5 ml (1.0 µCi) of 125I-BSA in PBS at a concentration of approximately 2 mg/ml was administered by i.v. injection, and tissues were extracted 1 h later. Mean permeability indices ± standard deviations were determined by dividing the 125I-BSA counts per minute per gram of tissue by the 125I-BSA counts per minute per milliliter of blood (n = 5). There was an overall difference in permeability between striated smooth muscle and brain (P < 0.0001) with the muscle values being higher than the brain values. There were also differences between strains (P = 0.0013) and between PTX- and carrier-treated mice (P < 0.0001). Significant interaction with PTX or carrier treatment (P = 0.0394) was also seen among the strains. In particular, SJL/J mice showed the largest difference between PTX and carrier treatment while C3H/HeJ and C3H.SJL-BphssD mice showed smaller and comparable differences.

PTX-induced hypersensitivity to histamine and serotonin. Previously, it was demonstrated that sensitization to histamine following PTX treatment is controlled by Bphs/Hrh1 (25). Therefore, we directly assessed the role of Bphs/Hrh1 in controlling hypersensitivity to serotonin (Table 2). Clearly, SJL/J and C3H.SJL-Bphs^sD mice are susceptible to histamine whereas C3H/HeJ mice are resistant. Similarly, SJL/J mice are susceptible to serotonin, but C3H/HeJ and C3H.SJL-Bphs^sD mice are equally resistant to serotonin at both 30 and 720 min postchallenge. These results demonstrate that the genetic control of susceptibility to vasoactive amine sensitization is vasoactive amine specific and that Bphs/Hrh1 does not play a role in controlling sensitivity to serotonin.

Our data are also consistent with susceptibility to vasoactive amine sensitization being a two-step process: an induction phase characterized by a 2- to 3-day latency period following intoxication and a rapid effector phase typified by a time to death due to hypotensive and hypovolemic shock of minutes to hours after challenge with the vasoactive agent (28, 29). Additionally, vasoactive amine sensitization is characterized by a period of hypersensitivity that lasts upward of 60 days (29, 30). This suggests that the induction phase is associated with the synthesis and storage of additional vasoactive factors within endothelial cells that are released upon exposure to vasoactive agents such as histamine or increased, protracted expression of H1R by cells. In this regard, it is known that inflammatory stimuli induce the synthesis and storage of interleukin-8, von Willebrand factor, P-selectin, endothelin, and CD63 in Weibel-Palade bodies within endothelial cells (41, 45) and that histamine and serotonin are secretagogues for the release of these agents (15, 34). Thus, in this model death due to hypotensive and hypovolemic shock following PTX sensitization and exposure to histamine is due to the combined direct vasodilatory effects of histamine and the actions of released stored products from Weibel-Palade bodies which together result in an insurmountable affront to the vascular endothelium. Without exposure to PTX the endothelial cells can compensate for the effects of histamine, since the animals do not die, but they cannot compensate for the amplified signaling through multiple receptors and synergistic second-messenger stimulation.

Transcriptional profiling following intoxication with catalytically active PTX and recombinant mutant ADP-ribosyltransferase inactive PTX has led to the identification of genes that are both unregulated and down regulated (5, 8). The early transcriptional response is dominated by the increased expression of a large number of cytokine and chemokine genes, DNA-binding proteins, and NF-B-regulated genes. Additionally, it was shown that 5-HTR_2A and 5-HTR_1E exhibit transcriptional changes following intoxication with PTX. Thus, genetic differences in susceptibility to serotonin sensitization may be a function of differential levels of 5-HTR subtype expression. In this regard, SJL/J and AKR/J mice are the prototype serotonin-susceptible strains, and susceptibility can be blocked with 5-HTR₂ receptor selective antagonists (unpublished data).

Enhancement of antigen-specific DTH. One of the principal immunomodulatory activities of PTX is its adjuvant activity. When PTX is used as an ancillary adjuvant at the time of immunization, it leads to enhanced and prolonged antigen-specific DTH responses (35). The DTH response elicited following immunization with PTX is mediated by CD4⁺ Th1 helper T cells that produce excessive amounts of the proinflammatory cytokine gamma interferon (36, 37). It was suggested that this is due to the direct effects of PTX on the responding T cells during sensitization such that they exhibit augmented production of gamma interferon at the time of challenge. Recent data, however, suggest that this may not be the case and that enhanced DTH responsiveness may be due to increased clonal expansion of Th1 helper T cells (38) driven by PTX activation of antigen-presenting cells (17, 33). C3H.SJL-Bphs^sD mice immunized with OVA emulsified in CFA and given PTX at the time of immunization exhibited significantly greater DTH responses at day 1 and day 5 post-antigen challenge than did C3H/HeJ mice (Fig. 4A).

View larger version (13K): [in this window] [in a new window]   FIG. 4. Bphs/Hrh1 controls enhancement of DTH responses elicited by PTX to both foreign antigen (A) and self antigen MOG 35-55 (B). C3H/HeJ and C3H.SJL-BphssD mice were sensitized with OVA while C57BL/6J and B6.129P-Hrh1tm1Wat mice were injected with MOG 35-55 emulsified in CFA. Immediately thereafter, each animal received PTX or carrier by i.v. injection. Seven days later the average thickness of the right pinna was determined by taking three measurements with a spring-loaded micrometer. Subsequently, each pinna was injected with 10 µl of physiological saline containing 1.0 mg of OVA or MOG 35-55/ml. Ear thickness measurements were taken at various times postchallenge, and the corrected average thickness was determined. Data are plotted as micrometers ± standard deviations. (A) Open bars, C3H/HeJ; solid bars, C3H.SJL-BphssD. The repeated-measure ANOVA for the DTH response to OVA revealed a statistically significant interaction (P < 0.0001) between the strain and the day postchallenge. In particular, C3H/HeJ and C3H.SJL-BphssD groups showed significantly different postchallenge changes in thickness (P < 0.0001). (B) , C57BL/6J mice immunized with MOG 35-55 emulsified in CFA plus PTX; , B6.129P-Hrh1tm1Wat mice immunized with MOG 35-55 emulsified in CFA plus PTX; , C57BL/6J mice immunized with MOG 35-55 emulsified in CFA without PTX. The repeated-measure ANOVA for the DTH response to MOG 35-55 indicated that the three groups had significantly different responses over the 5 days postchallenge as reflected in an overall significant group by time interaction (P < 0.0001). Orthogonal decompositions of the time effects indicated that the linear effect (P < 0.0001) and quadratic effect (P = 0.0003) differed among the three groups with the C57BL/6J mice immunized with MOG 35-55 emulsified in CFA plus PTX showing a positive increase with a leveling out after day 1 while C57BL/6J mice immunized without PTX and B6.129P-Hrh1tm1Wat mice treated with PTX had decreasing values over time.

Summary. Overall, the results of this study indicate that Bphs/Hrh1 does not play a significant role in the genetic control of susceptibility to toxicity, serotonin sensitization, or histamine-independent increased vascular permeability following in vivo intoxication. Similarly, there was no significant difference in responsiveness to PTX as assessed by the induction of hypoglycemia or refractivity to hyperglycemia following exposure to epinephrine or in the leukocytosis response between C3H/HeJ and C3H.SJL-Bphs^sD or C57BL/6J and B6.129P-Hrh1^tm1Wat mice following intoxication. Differences in the total WBC counts observed among the strains studied reflected differences in the basal WBC counts among the inbred strains. In contrast, Bphs/Hrh1 clearly controls susceptibility to PTX-induced hypersensitivity to histamine and enhancement of antigen-specific DTH responses mediated by CD4⁺ Th1 helper T cells.

Our results indicate that phenotypic variation in responsiveness to PTX reflects the genetic control of intermediate phenotypes rather than a generalized refractivity to PTX intoxication. This interpretation is consistent with two observations. First, unlike receptors for many bacterial toxins, a single molecular entity functioning as a receptor for PTX has not been identified. Rather, PTX appears to bind to common carbohydrate motifs shared by various glycoproteins and glycolipids, thereby enabling the intoxication of virtually all cells, albeit at different rates (10, 19). The second observation is that transcriptional profiling studies revealed a remarkably consistent, highly stereotyped response by peripheral blood mononuclear cells following exposure to B. pertussis and PTX rather than highly individualized responses (8, 17). Thus, studies designed to delineate the mechanisms and genetics underlying the pathological complications associated with B. pertussis infection and adverse reactions observed following vaccination require assessment of each of the intermediate phenotypes elicited by in vivo intoxication rather than global approaches designed to assess responsiveness to B. pertussis or PTX in general.

	ACKNOWLEDGMENTS

 
This work was supported by National Institutes of Health grants NS36526, AI4515, and AI41747 and National Multiple Sclerosis Society grant RG-3129.

	FOOTNOTES

 
* Corresponding author. Mailing address: C317 Given Medical Bldg., University of Vermont, Burlington, VT 05405. Phone: (802) 656-3270. Fax: (802) 656-3854. E-mail: cteusche{at}zoo.uvm.edu.

Editor: J. T. Barbieri

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